COVID-19 FDA Response: Guidance on Protocol Amendments and Clinical Study Reports in Affected Ongoing Trials

Clinical Researcher—August 2020 (Volume 34, Issue 7)


Jack Modell, MD


As the world continues to navigate the many impacts of the novel coronavirus that causes COVID-19, the clinical research industry has seen an increase in new trials for the development of COVID-19-related treatments and products. On the other hand, some ongoing and planned clinical trials not related to COVID-19 have experienced operational interruptions, subsequently compromising the ability to collect meaningful, reliable, and accurate data, and in some cases jeopardizing the overall integrity of the trial.

These incidents have presented the need for protocol modifications to adjust for COVID-19 control measures and COVID-19 illness. The U.S. Food and Drug Administration (FDA) recently developed the “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” to offer advice on managing protocol amendments and deviations, as well as for documenting changes to the trial.

This column will discuss a few of the common challenges in conducting research that is not related to the pandemic during this time, as well as the current recommendations offered in the new FDA guidance. More detailed information on these and other COVID-19-related challenges can be found via the hyperlinks at the end of the column.

Subject Discontinuations and Assuring the Safety of Trial Participants

The uncertainty of the evolving pandemic brings with it a variety of potential roadblocks to current trials, including a decrease in willing participants, travel restrictions, and staff reductions at study sites. Understandably, study participants are expressing a reluctance to visit healthcare settings out of concern of contracting COVID-19. As a result, some trials are experiencing an increase in missed visits or dropouts, and some studies have limited new enrollment and are focusing on subjects already in the trial.

FDA recognizes that protocol modifications may help mitigate the limitations imposed by the COVID-19 emergency, the nature of which will depend on many factors, including the disease under study, trial design, and specific difficulties that have been encountered in conducting the study. FDA underscores that sponsors must foremost continue to assure the safety of trial participants, as well as to maintain compliance with Good Clinical Practice (GCP) and minimize risks to trial integrity.

Depending on the specific circumstances of the trial, FDA states that sponsors—along with clinical investigators and institutional review boards (IRBs)—may determine that the protection of a study participant’s safety, welfare, and rights, while maintaining study integrity, is best served by any of the following:

  • Continuing to participate in the trial as per protocol
  • Discontinuing the administration or use of an investigation product
  • Discontinuing participation in the trial
  • Implementation of alternative processes or procedures that do not conflict with the requirements and limitations of the existing protocol
  • Modifying study protocols and documenting the modifications in protocol amendments (protocol modifications should not be implemented prior to IRB approval unless required to eliminate or reduce an immediate safety risk for a subject, nor should they be implemented prior to consultation with the relevant reviewing division at FDA for modifications that involve study endpoints or statistical analysis)

Modifying Assessment Methods

As study participants hesitate to visit healthcare facilities, the decrease in onsite visits makes it difficult to collect data from important assessments, including efficacy outcome measures and those required for patient safety, like visual examinations, vital signs, and procedures such as ECG or MRI. To help mitigate these challenges, FDA recommends that sponsors evaluate whether alternative methods to gather this information are possible. Examples include phone contact, virtual visits, in-home visits by a qualified professional, and use of local labs or diagnostic centers. These alternative methods are only suitable, however, in cases where the data can be objectively and adequately obtained and where subjects incur no increase in risk due to assessment delays or limitations.

Potential Impacts on Clinical Study Results

Regardless of the specific modifications made to the assessment process, FDA emphasizes the need for sponsors to clearly document all changes to study conduct, the reasons behind them, and how COVID-19 influenced these changes. Many of these impacts, such as missed visits, may be captured as protocol deviations, while others may be documented as changes to the monitoring plan, findings in site visit monitoring reports, or data within the electronic data capture system.

Because changes in study requirements, allowances, and visit schedules (as well as missed visits or patient discontinuations) may fundamentally affect the ability of the study to yield valid and interpretable results, full documentation of all of these details in the clinical study reports is of utmost importance, as it allows both FDA and sponsors to look back to determine the extent to which the pandemic and associated modifications might have affected the overall outcome of the trial.

Additionally, the rationale for any changes to the protocol should be documented in all amendments. Further, as noted above, if an amendment to a study that is intended to provide data to support registration requires amending the data management and/or statistical analysis plans, or otherwise fundamentally changes the study design or analysis, FDA recommends consulting the appropriate review division before making the changes.


As knowledge of the new coronavirus continues to evolve, sponsors must understand the practical limitations that exist and seriously consider what modifications might be necessary to assure patient safety, compliance with GCP, and the integrity of ongoing trials. Fortunately, today’s technology has provided new ways of working around these challenges, with perhaps the most notable being the rise of video conferencing and telemedicine.

By considering FDA’s recommendations and by complying with current regulations, sponsors can mitigate the risks on study conduct and integrity imposed by the current pandemic and continue working toward discovering new therapies for unmet medical needs.

Additional information on COVID-19-related challenges in drug development can be found via the following links:

Jack Modell, MD, is Vice President and Senior Medical Officer for Rho, and is a board-certified psychiatrist with approximately 40 years of experience in clinical research.